Forkhead box (FOX) proteins are a large family of transcription factors with diverse functions in development, aging and cancer. Recently, using Foxp1 conditional knock-out mice in which all Foxp1 isoforms are deleted, we found that loss of Foxp1 results in the abnormal development of T cells. During the transition from double-positive (DP) stage to single-positive (SP) stage in the thymus, Foxp1-deficient SP thymocytes acquire an activated phenotype prematurely and develop into peripheral CD4+ T and CD8+ T cells that exhibit an activated phenotype, increased apoptosis and readily produce cytokines upon T cell receptor (TCR) engagement. These data identify Foxp1 as a novel essential player in the generation of quiescent na[unreadable]ve T cells during thymocyte development. Based on our most recent findings, we hypothesize that Foxp1 also plays a critical role in regulating T cell activation. Specifically, the proposed studies will address: 1) Which TCR signaling pathway(s) does Foxp1 impact in regulating T cell activation? 2) What are the key targets of Foxp1 in T cells? 3) What are the critical roles of Foxp1 in mature T cell responses in vivo? Whereas regulating TCR signaling pathway(s) could be part of the mechanism of how Foxp1 regulates T cell activation, the research proposed will also define other Foxp1-dependent functions by delineating global changes in gene expression that contribute to the abnormal activated phenotype of Foxp1-deficient T cells and identifying Foxp1 target genes. Knowledge obtained from these studies will provide novel information for the design of new therapeutic strategies designed to manipulate T cell activation for the treatment of autoimmune and infectious diseases, cancer, and in vaccine development.